Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important.
Trang 1R E S E A R C H A R T I C L E Open Access
Serum HMGB1 as a prognostic marker for
malignant pleural mesothelioma
Chiharu Tabata1*†, Eisuke Shibata1†, Rie Tabata2, Shingo Kanemura1, Koji Mikami1, Yoshitaka Nogi1,
Eriko Masachika1, Tomoyuki Nishizaki3and Takashi Nakano1
Abstract
Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy Therefore, diagnosing MPM early is very important Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis MPM involves the malignant transformation of mesothelial cells, which originate from
mesenchymal cells similar to lung fibroblasts Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM Methods: HMGB1 production from MPM cell lines was measured using ELISA Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases
Results: HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the
population who had been exposed to asbestos but had not developed MPM The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant Conclusions: Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM
Keywords: Mesothelioma, Tumor marker, HMGB1
Background
Malignant pleural mesothelioma (MPM) is an aggressive
malignant tumor of mesothelial origin, which shows a
limited response to conventional chemotherapy and
ra-diotherapy [1-3] Although the multi-target antifolate
pemetrexed was recently approved as a first-line agent
in combination with cisplatin for the treatment of MPM,
the overall survival of MPM patients remains very poor
[4] with a median survival duration of 8–18 months [5]
In several centers, potentially curative surgery combined
with some form of adjuvant therapy has been performed
Therefore, diagnosing MPM at an early stage is very
important [1] However, diagnosis by radiological and/
or histological examinations can often be very difficult
Therefore, efficient and practical serum biomarkers are required to aid the diagnosis of MPM
In the diagnosis of lung cancer, serum markers such as CEA, CYFRA, proGRP, and SCC are useful There have been several reports about candidates for clinically use-ful markers for MPM Indeed, some of them have been reported to be useful serum markers for MPM, such as mesothelin [6,7]; however, little is known about their biological functions or effects on MPM cells For further improvements in the specificity and sensitivity of diag-nosis, research into the development of novel biological markers for MPM is urgently required
High-mobility group box 1 (HMGB1) is a member of the high-mobility group protein super-family playing an important role in a variety of biological processes such
as transcription, DNA repair, proliferation, and inflamma-tion [8,9] Some researchers have previously reported that HMGB1 was correlated with pulmonary fibrosis [10,11] Hamada and colleagues demonstrated that HMGB1 pro-tein was predominantly detected in fibrotic lesions of lung
* Correspondence: ctabata@hyo-med.ac.jp
†Equal contributors
1 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo
College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501,
Japan
Full list of author information is available at the end of the article
© 2013 Tabata et al.; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
Trang 2tissues in patients with idiopathic pulmonary fibrosis and
was increased in bleomycin-treated mouse lung tissues
compared to that in control tissues Moreover, they found
that HMGB1 induced lung fibroblast proliferation, which
may be the underlying mechanism of pulmonary fibrosis
[11] MPM involves the malignant transformation of
me-sothelial cells, which originate from mesenchymal cells
similar to lung fibroblasts Here, we investigated serum
levels of HMGB1 in patients with MPM and compared
them with those of a population that had been exposed to
asbestos without MPM
Methods
Cell culture
Human malignant pleural mesothelioma cell lines H28
(epithelioid), H2052 (sarcomatoid), H2452 (biphasic),
and MSTO-211H (biphasic) and the human mesothelial
cell line MeT-5A were obtained from the American
Type Culture Collection (Rockville, MD) These cells
were cultured in RPMI 1640 (Sigma Chemical Co., St
Louis, MO) supplemented with 10% heat-inactivated
fetal calf serum The cell viability at 24 hours of culture
was above 95% The cell density was confluent
Patients and serum samples
We studied HMGB1 levels in sera collected from 106
individuals who presented at the Department of
Res-piratory Medicine of Hyogo College of Medicine
Hospi-tal from 2005 to 2009 All individuals had a documented
asbestos exposure history Sixty-one individuals had
malignant pleural mesothelioma, which was examined
by video-assisted thoracic surgery and diagnosed using
histopathological samples by pathologists skilled in the
diagnosis of MPM All patients were classified according
to the staging system of the International Mesothelioma
Interest Group (IMIG) [12] Forty-five individuals had
benign asbestos-related diseases (asbestosis or pleural
plaques) or were healthy despite their previous asbestos
exposure We examined the patients with lung cancer
in-volving malignant pleural effusion (n=11, age: 65.6 ± 5.8,
male/female: 5/6, adenocarcinoma/ squamous cell
carcin-oma: 8/3) This study was approved by Ethics Committee
of Hyogo College of Medicine in accordance with the
1975 Declaration of Helsinki Informed consent was
ob-tained from all patients Serum samples were collected
be-fore treatment, immediately frozen in liquid nitrogen, and
stored at−80 degrees Celsius until use
Measurement of HMGB1
HMGB1 concentrations of cultured supernatants from
cell lines and serum samples were measured using an
enzyme-linked immunosorbent assay (ELISA) Kit II
(Shino-Test, Tokyo, Japan) according to the
manufac-turers’ instructions
Statistical analysis
The nonparametric Mann–Whitney U-test was used to compare two groups of serum samples In all tests, a p-value <0.05 was considered significant In order to esti-mate the significance of serum HMGB1 values, receiver operating characteristic (ROC) curves, area under the ROC curves (AUC), and their 95% confidence intervals (95% CI) were calculated using standard techniques To obtain ap-propriate serum level cut-off values, we calculated the total sensitivity and specificity for each cut-off value and then chose cut-off values that maximized the sum of sensitivity plus 1-specificity Estimates of the probability of survival were calculated by the Kaplan-Meier method and com-pared using the log-rank test In order to evaluate the prognostic significance of HMGB1 with regard to the sur-vival of patients with MPM, Cox’s proportional hazards regression analysis (backward) was carried out as multi-variate analysis We used StatMate and Statcel software
Results
Evaluation of HMGB1 production in mesothelioma and mesothelial cells
We evaluated HMGB1 production in four mesothelioma cell lines and a mesothelial cell line by ELISA As shown
in Figure 1, HMGB1 was produced in all cells H28 and H2052 cells were demonstrated to produce significantly more HMGB1 (4.3±0.5 and 4.6±0.2 ng/106 cells, res-pectively) than that of H2452, MSTO-211H, and MeT-5A cells (1.7±0.2, 0.8±0.2, and 1.7±0.2 ng/106 cells, respec-tively) (p< 0.01, p< 0.01, respecrespec-tively)
Serum levels of HMGB1 in patients with MPM, those with benign asbestos-related diseases (asbestosis or pleural plaques), and healthy individuals with a history of asbestos exposure
We recruited a total of 106 subjects with a history of asbestos exposure Of them, 61 had confirmed MPM, 26
Figure 1 Evaluation of HMGB1 production in mesothelioma and mesothelial cells H28, H2052, H2452, MSTO-211H mesothelioma cell lines and human mesothelial cell line MeT-5A were cultured for 24 hours in serum-free medium The concentration of HMGB1 in the culture supernatant of all cells was measured as described in the Methods Results are indicated as the mean ± SD of three separate experiments in triplicate The Bonferroni/Dunn multiple comparisons test was used.
Trang 3had pleural plaques and/or asbestosis, and 19 had no
asbestos-related lesions despite being exposed to
asbes-tos; i.e., were healthy Their characteristics are shown in
Table 1
The ROC curves for serum HMGB1 levels showed
that patients with MPM had an AUC of 0.674 relative to
those with benign asbestos-related diseases (asbestosis
or pleural plaques) and those who were healthy despite
asbestos exposure (95% CI: 0.589-0.758) At the
opti-mal cut-off value of 9.0 ng/ml, diagnostic sensitivity was
34.4% and specificity was 100% (Figure 2A) The positive
predictive value (PPV) was 100%, and the negative
pre-dictive value (NPV) was 52.9% Serum HMGB1
concen-trations of patients with MPM were significantly higher
(median: 6.7, interquartile range: 4.8-11.0 ng/ml) than
those of patients with benign asbestos-related diseases
(asbestosis or pleural plaques) and healthy individuals
(median: 5.4, interquartile range: 4.0-6.7 ng/ml) (p=0.001,
Figure 2B) However, there were no significant
diffe-rences between serum HMGB1 levels of MPM
histo-logical groups (sarcomatoid: (median: 4.9, interquartile
range: 4.5-14.6 ng/ml, non- sarcomatoid: median: 6.7,
inter-quartile range: 4.9-10.0ng/ml) (p=0.68) or different disease
stages (stage I: median: 5.7, interquartile range: 5.5-7.3
ng/ml, stage II: median: 7.4, interquartile range: 4.9-9.9
ng/ml, stage III: median: 5.9, interquartile range: 4.7-6.2
ng/ml, and stage IV: median: 8.2, interquartile range:
4.5-12.7 ng/ml) and age (65≤: median: 6.2, interquartile
range: 4.7-9.4 ng/ml and 65 years>: median: 6.9,
inter-quartile range: 5.5-11.0 ng/ml, respectively) On the other
hand, there were no significant differences between serum HMGB1 levels of MPM and patients with lung cancer in-volving malignant pleural effusion (n=11, age: 65.6 ± 5.8, male/female: 5/6, adenocarcinoma/ squamous cell carcin-oma: 8/3) (median: 7.0, interquartile range: 5.5-10.4 ng/ml) (p=0.75)
Relationship between HMGB1 and overall survival
We were able to closely follow-up 61 patients (median:
328, interquartile range: 176–501, min: 23, max: 1400 days) To study the relationship between serum HMGB1 levels and patients’ clinical courses, we separated pa-tients based on their serum HMGB1 levels at the time of the first measurement The first group included patients with serum HMGB1 levels lower than 9.0 ng/ml, the cut-off value that we used In this group of 40 patients, the mean serum HMGB1 value was 5.4 ng/ml (interquar-tile range: 4.5-6.7) The other group included the re-maining 21 patients with serum HMGB1 levels higher than 9.0 ng/ml, whose mean serum HMGB1 value was
Table 1 Characteristics of MPM patients and non-MPM
subjects with a history of asbestos exposure
MPM
Gender Male / Female 44(72.1)/ 17(27.9) 61
Histology Epithelioid 43(70.6)
Desmoplastic 3(4.9)
Stage I / II / III / IV 7(11.5)/ 6(9.8) /
11(18.0) / 37(60.7) Non-MPM*
Gender Male / Female 39(86.7) / 6(13.3) 45
Plaque and asbestosis 2(4.5)
*All individuals were exposed to asbestos.
Figure 2 Serum HMGB1 levels in patients with MPM and non-MPM subjects (A) Sensitivity and specificity of serum HMGB1 for distinguishing patients with MPM from non-MPM subjects (ROC curve) An analysis that included 61 MPM patients and 45 non-MPM subjects with a history of asbestos exposure revealed an AUC of 0.674 (95% CI: 0.589-0.758) At a cut-off value of 9.0 ng/ml, diagnostic sensitivity was 34.4% and specificity was 100% (B) Serum HMGB1 levels in non-MPM subjects and MPM patients were measured as described in the Methods.
Trang 427.4 ng/ml (interquartile range: 10.3-18.4) The difference
in overall survival between the two groups was
signifi-cant (p=0.03, Figure 3) Cox’s regression analysis was
performed on 61 MPM patients for whom data on age,
gender, histology, stage, and serum HMGB1 level were
available, and an independent significant prognostic effect
of serum HMGB1 level ( ≥9.0 ng/ml versus < 9.0 ng/ml;
HR, 2.1; 95% CI: 1.0-4.4; p=0.05) and stage (IV≥ versus <
I-III; HR, 2.6; 95% CI: 1.1-6.1; p=0.03) on survival was
found
Discussion
HMGB1 acts as an extra-cellular signaling molecule
as-sociated with inflammation, cell proliferation, cell
migra-tion, and cell differentiation [8,9] In all mammalian
cells, HMGB1 is present in the nucleus and is released
from necrotic cells, activated macrophages, and
den-dritic cells, binding with high affinity to some receptors
such as the receptor for advanced glycation end
prod-ucts (RAGE), mediating the response to infection and
injury, resulting in the promotion of inflammation [13]
Clinically, several reports have suggested that HMGB1
contributes to a number of diseases including diabetic
complications [14], immune/inflammatory disorders
[14], sepsis [15], heart failure [16], rheumatoid arthritis
[17], cystic fibrosis airway disease [18], and tumor
biol-ogy [14,19]
Over-expression of HMGB1 is associated with the
hallmark of cancer such as unlimited potential for
repli-cation, angiogenesis, apoptosis, self-sufficiency in growth
signals, insensitivity to antigrowth signals, inflammatory
microenvironment, tissue invasion, and metastasis [20]
Taguchi and colleagues demonstrated that blockade of
RAGE-HMGB1 signaling suppressed tumor growth and
metastasis [21] Recent studies have reported that
HMGB1 activity is found in several cancers such as
mel-anoma [22], colon cancer [23], breast cancer [24], and
lung cancer [25] However, the relationship between
HMGB1 and MPM has not been fully investigated
It is well known that MPM is associated with asbestos
exposure [1-3] The lifetime risk of MPM is closely
re-lated to an occupational and/or environmental asbestos
exposure history [26] Although asbestos usage has re-cently been banned in Western countries and Japan, the incidence of MPM is expected to markedly increase over the next few decades because there is a long latency pe-riod (20–40 years) between asbestos exposure and tumor development [27] Inflammation is the hallmark of asbes-tos exposure in organs and contributes to asbesasbes-tos car-cinogenesis [28,29] Asbestos exposure induces human mesothelial cell necrosis with the resultant release of HMGB1 in the extra-cellular space HMGB1 causes a chronic inflammatory response, accumulation of macro-phages and other inflammatory cells, and the secretion of TNF-alpha from these cells, which induces NF-kB activa-tion, leading to the survival and transformation to MPM
of human mesothelial cells [30] Therefore, HMGB1 is an important key modulator of MPM development
In this study, we first examined HMGB1 production in MPM cells and found that mesothelioma cells such as H28 (epithelioid) and H2052 (sarcomatoid) produced higher levels of HMGB1 protein than that of human mesothelial cell line MeT-5A
Next, we evaluated the clinical role of serum HMGB1
in MPM and showed that patients with MPM had sig-nificantly higher serum levels of HMGB1 than the non-MPM population with a history of asbestos exposure, which suggests its usefulness as a marker for MPM Al-though the diagnostic sensitivity of HMGB1 for MPM measured on an ROC curve was not high (34.4%), its specificity and PPV was extremely high (100%, 100%, re-spectively), suggesting that high serum HMGB1 levels are supportive of a differential diagnosis of MPM In vitro study, sarcomatiod type DMPM cells produced HMGB1 However, there were no significant differen-ces between serum HMGB1 levels of MPM histological groups Moreover, the Kaplan-Meier method revealed a significant correlation between serum HMGB1 levels and survival, which suggests its usefulness as a marker for estimating prognosis Serum mesothelin is currently considered the best available serum biomarker of malig-nant pleural mesothelioma [7] So the further examin-ation about serum HMGB1 in MPM is needed
Since the clinical stage of MPM is not related to the presence or absence of pleural effusion, and early distinction of MPM patients from those with benign asbestos-related diseases is necessary, we propose that measuring serum HMGB1 levels is an easy and useful method for the clinical management for MPM
Conclusion
In summary, we have demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than a population with a history of asbestos exposure that did not develop MPM, and that the difference in
Figure 3 Survival of MPM subjects according to serum HMGB1
levels Estimates of the probability of survival were calculated using
the Kaplan-Meier method and compared using the log-rank test.
Trang 5overall survival between groups with serum HMGB1
levels that were lower and higher than assumed cut-off
values was significant It is suggested that HMGB1 might
be a useful serum prognostic factor for MPM The
further examination about serum HMGB1 in MPM is
needed
Abbreviations
AUC: Area under the ROC curve; CI: Confidence interval; ELISA:
Enzyme-linked immunosorbent assay; HMGB1: High-mobility group box 1;
MPM: Malignant pleural mesothelioma; PPV: Positive predictive value;
RAGE: Receptor for advanced glycation end products; ROC: Receiver
operating characteristic.
Competing interests
We declare that no conflicts of interest exist.
Authors ’ contribution
TC, TR and NT designed the research TC, SE and TR performed the research.
TC, MK, KS, NY and ME collected data TC and TR analyzed and interpreted
data TC performed statistical analysis TC and TR wrote the manuscript.
All authors read and approved the final manuscript.
Acknowledgements
We thank Ms Hidemi Kitai for providing technical assistance.
Funding
This work was supported by grants from KAKENHI, a Grant-in-Aid for
Scientific Research (C) (23591167) and Health Labour Sciences Research
Grant.
Author details
1 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo
College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501,
Japan 2 Department of Internal Medicine, Hyogo Prefectural Tsukaguchi
Hospital, Hyogo, Japan 3 Division of Bioinformation, Department of
Physiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Received: 9 December 2012 Accepted: 18 April 2013
Published: 24 April 2013
References
1 Robinson BW, Musk AW, Lake RA: Malignant mesothelioma Lancet 2005,
366:397 –408.
2 Robinson BW, Lake RA: Advances in malignant mesothelioma N Engl J
Med 2005, 353:1591 –1603.
3 Wagner JC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and
asbestos exposure in the North Western Cape Province Br J Ind Med
1960, 17:260 –271.
4 Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P,
Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P: Phase III
study of pemetrexed in combination with cisplatin versus cisplatin alone
in patients with malignant pleural mesothelioma J Clin Oncol 2003,
21:2636 –2644.
5 Nowak AK, Lake RA, Kindler HL, Robinson BW: New approaches for
mesothelioma: biologics, vaccines, gene therapy, and other novel
agents Semin Oncol 2002, 29:82 –96.
6 Robinson BW, Creaney J, Lake R, Nowak A, Musk AW, de Klerk N, Winzell P,
Hellstrom KE, Hellstrom I: Mesothelin-family proteins and diagnosis of
mesothelioma Lancet 2003, 362:1612 –1616.
7 Hollevoet K, Reitsma JB, Creaney J, et al: Serum mesothelin for diagnosing
malignant pleural mesothelioma: an individual patient data meta-analysis.
J Clin Oncol 2012, 30:1541 –1549.
8 Bianchi ME, Beltrame M, Paonessa G: Specific recognition of cruciform
DNA by nuclear protein HMG1 Science 1989, 243(4894 Pt 1):1056 –1059.
9 Scaffidi P, Misteli T, Bianchi ME: Release of chromatin protein HMGB1 by
necrotic cells triggers inflammation Nature 2002, 418(6894):191 –195.
10 He M, Kubo H, Ishizawa K, Hegab AE, Yamamoto Y, Yamamoto H,
Yamaya M: The role of the receptor for advanced glycation
end-products in lung fibrosis Am J Physiol Lung Cell Mol Physiol 2007, 293:L1427 –L1436.
11 Hamada N, Maeyama T, Kawaguchi T, Yoshimi M, Fukumoto J, Yamada M, Yamada S, Kuwano K, Nakanishi Y: The role of high mobility group box1 in pulmonary fibrosis Am J Respir Cell Mol Biol
2008, 39:440 –447.
12 Rusch VW: A proposed new international TNM staging system for malignant pleural mesothelioma From the International Mesothelioma Interest Group Chest 1995, 108:1122 –1128.
13 Lotze MT, Tracey KJ: High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal Nat Rev Immunol 2005, 5:331 –3342.
14 Schmidt AM, Yan SD, Yan SF, Stern DM: The multiligand receptor RAGE as
a progression factor amplifying immune and inflammatory responses.
J Clin Invest 2001, 108:949 –955.
15 Qin S, Wang H, Yuan R, Li H, Ochani M, Ochani K, Rosas-Ballina M, Czura CJ, Huston JM, Miller E, Lin X, Sherry B, Kumar A, Larosa G, Newman W, Tracey KJ, Yang H: Role of HMGB1 in apoptosis-mediated sepsis lethality.
J Exp Med 2006, 203:1637 –1642.
16 Takahashi K, Fukushima S, Yamahara K, Yashiro K, Shintani Y, Coppen SR, Salem HK, Brouilette SW, Yacoub MH, Suzuki K: Modulated inflammation
by injection of high-mobility group box 1 recovers post-infarction chronically failing heart Circulation 2008, 118(14 Suppl):S106 –S1014.
17 Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M, Inoue K, Yamada S, Ijiri K, Matsunaga S, Nakajima T, Komiya S, Maruyama I: High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine Arthritis Rheum
2003, 48:971 –981.
18 Rowe SM, Jackson PL, Liu G, Hardison M, Livraghi A, Solomon GM, McQuaid DB, Noerager BD, Gaggar A, Clancy JP, O'Neal W, Sorscher EJ, Abraham E, Blalock JE: Potential role of high-mobility group box 1 in cystic fibrosis airway disease Am J Respir Crit Care Med 2008, 178:822 –831.
19 Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, Lotze MT: Masquerader: high mobility group box-1 and cancer Clin Cancer Res
2007, 13:2836 –2848.
20 Tang D, Kang R, Zeh HJ 3rd, Lotze MT: High-mobility group box 1 and cancer Biochim Biophys Acta 2010, 1799:131 –140.
21 Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla
E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa
S, Stern DM, Schmidt AM: Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases Nature 2000, 405:354 –360.
22 Poser I, Golob M, Buettner R, Bosserhoff AK: Upregulation of HMG1 leads
to melanoma inhibitory activity expression in malignant melanoma cells and contributes to their malignancy phenotype Mol Cell Biol 2003, 23:2991 –2998.
23 Völp K, Brezniceanu ML, Bösser S, Brabletz T, Kirchner T, Göttel D, Joos S, Zörnig M: Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas Gut 2006, 55:234 –242.
24 Brezniceanu ML, Völp K, Bösser S, Solbach C, Lichter P, Joos S, Zörnig M: HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma FASEB J 2003, 17:1295 –1297.
25 Liu PL, Tsai JR, Hwang JJ, Chou SH, Cheng YJ, Lin FY, Chen YL, Hung CY, Chen WC, Chen YH, Chong IW: High-mobility group box 1-mediated matrix metalloproteinase-9 expression in non-small cell lung cancer contributes to tumor cell invasiveness Am J Respir Cell Mol Biol 2010, 43:530 –538.
26 Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J:
Occupational, domestic and environmental mesothelioma risks in the British population: a case –control study Br J Cancer 2009, 100:1175 –1183.
27 Selikoff IJ, Hammond EC, Seidman H: Latency of asbestos disease among insulation workers in the United States and Canada Cancer 1980, 15:2736 –2740.
28 Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, Franzoso G, Carbone M: TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis Proc Natl Acad Sci USA 2006, 103:10397 –10402.
Trang 629 Carbone M, Ly BH, Dodson RF, Pagano I, Morris PT, Dogan UA, Gazdar AF,
Pass HI, Yang H: Malignant mesothelioma: facts, myths, and hypotheses.
J Cell Physiol 2012, 227:44 –58.
30 Carbone M, Yang H: Molecular pathways: targeting mechanisms of
asbestos and erionite carcinogenesis in mesothelioma Clin Cancer Res
2012, 18:598 –604.
doi:10.1186/1471-2407-13-205
Cite this article as: Tabata et al.: Serum HMGB1 as a prognostic marker
for malignant pleural mesothelioma BMC Cancer 2013 13:205.
Submit your next manuscript to BioMed Central and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at